CN107759619A - A kind of dihydropyran and thiazole cycle compound and its production and use - Google Patents
A kind of dihydropyran and thiazole cycle compound and its production and use Download PDFInfo
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- CN107759619A CN107759619A CN201711041409.8A CN201711041409A CN107759619A CN 107759619 A CN107759619 A CN 107759619A CN 201711041409 A CN201711041409 A CN 201711041409A CN 107759619 A CN107759619 A CN 107759619A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 152
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 title claims abstract description 11
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 title abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 79
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 239000000758 substrate Substances 0.000 claims description 10
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 9
- 229910052710 silicon Inorganic materials 0.000 claims description 9
- 239000010703 silicon Substances 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 150000003557 thiazoles Chemical class 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 235000015177 dried meat Nutrition 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 230000000118 anti-neoplastic effect Effects 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 150000003335 secondary amines Chemical class 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 1
- 239000013078 crystal Substances 0.000 claims 1
- 210000005075 mammary gland Anatomy 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 135
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 35
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- 238000001819 mass spectrum Methods 0.000 description 35
- 239000007787 solid Substances 0.000 description 35
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 32
- 239000011734 sodium Substances 0.000 description 28
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 16
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229960001866 silicon dioxide Drugs 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- -1 Hydrogen pyrans Chemical class 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- QIOZLISABUUKJY-UHFFFAOYSA-N Thiobenzamide Chemical compound NC(=S)C1=CC=CC=C1 QIOZLISABUUKJY-UHFFFAOYSA-N 0.000 description 3
- 201000008275 breast carcinoma Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 229930192474 thiophene Natural products 0.000 description 3
- 0 *[C@](C12CC1)C1(CC1)Oc1c2[s]c(*)n1 Chemical compound *[C@](C12CC1)C1(CC1)Oc1c2[s]c(*)n1 0.000 description 2
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical compound COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 description 2
- RCSXKMHEVUZNQL-UHFFFAOYSA-N 2h-1,3-thiazol-5-one Chemical compound O=C1SCN=C1 RCSXKMHEVUZNQL-UHFFFAOYSA-N 0.000 description 2
- SUISZCALMBHJQX-UHFFFAOYSA-N 3-bromobenzaldehyde Chemical compound BrC1=CC=CC(C=O)=C1 SUISZCALMBHJQX-UHFFFAOYSA-N 0.000 description 2
- SRWILAKSARHZPR-UHFFFAOYSA-N 3-chlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1 SRWILAKSARHZPR-UHFFFAOYSA-N 0.000 description 2
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 2
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 2
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 238000001815 biotherapy Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- DTUQWGWMVIHBKE-UHFFFAOYSA-N phenylacetaldehyde Chemical compound O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- ZGTFNNUASMWGTM-UHFFFAOYSA-N 1,3-thiazole-2-carbaldehyde Chemical compound O=CC1=NC=CS1 ZGTFNNUASMWGTM-UHFFFAOYSA-N 0.000 description 1
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 1
- 241001269238 Data Species 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 108010021848 cyclosomatostatin Proteins 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- FXHGMKSSBGDXIY-UHFFFAOYSA-N heptanal Chemical compound CCCCCCC=O FXHGMKSSBGDXIY-UHFFFAOYSA-N 0.000 description 1
- JARKCYVAAOWBJS-UHFFFAOYSA-N hexanal Chemical compound CCCCCC=O JARKCYVAAOWBJS-UHFFFAOYSA-N 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229940100595 phenylacetaldehyde Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides dihydropyran of the one kind as shown in formula (I) and thiazole cycle compound；Additionally provide the preparation method for preparing aforesaid compound；The compounds process for production thereof of the present invention is easy, reaction is gentle, high income, and has certain antitumor activity, has wide market application foreground.
Description
Technical field
The present invention relates to a kind of dihydropyran and thiazole cycle compound and its production and use.
Background technology
Thiazole ring skeleton is widely present in natural products, synthetic drug, and correlative study shows the chemical combination containing the skeleton
Thing has a variety of important bioactivity and pharmaceutical activity, the derivative of substituent modification, analogue to such compound
Change and further biological activity, which revalue, becomes study hotspot.
How the dihydropyran of easy preparations high income simultaneously thiazole cycle compound is current Research Challenges.
The content of the invention
It is an object of the invention to provide a kind of dihydropyran and thiazole cycle compound and its production and use.
Present invention firstly provides dihydropyran of the one kind as shown in formula (I) and thiazole cycle compound：
Wherein, R1、R2It is independently selected from heterocycle, phenyl ring or there is substituent phenyl ring；
R3For hydrogen, C1-C10Alkane or phenyl ring；
R4For hydrogen or hydroxyl.
Further, above-claimed cpd has formula (I -1) or formula (I -2) structure：
Further, the compound is one of following compound：
Present invention also offers the preparation method of above-claimed cpd, it is characterised in that：Comprise the following steps：
(1) modus ponens (1) compound, chloracetyl chloride and sodium acid carbonate, with dichloromethane：Water=3:1 is solvent, 0 ± 3
Reacted at DEG C, produce formula (3) intermediate；Formula (4) compound and triethylamine are added into formula (3) intermediate, in 70 ± 3 DEG C of reactions
Afterwards, formula (5) thiazoles substrate is produced；
(2) modus ponens (5) thiazoles substrate, formula (6) compound and chiral amines catalyst, with tetrahydrofuran：Water=10:1
For solvent, after 25 ± 3 DEG C of reactions, compound shown in formula (I -1) is produced；
(3) compound, BFEE and triethyl group silicon hydrogen shown in modus ponens (I -1), react at 25 ± 3 DEG C, produce
Compound shown in formula (I -2).
Further, R1、R2It is independently selected from heterocycle, phenyl ring or there is substituent phenyl ring；R3For hydrogen, C1-C10Alkane
Or phenyl ring.
Further, in step (1), formula (1) compound is 1 with the mol ratio of chloracetyl chloride and sodium acid carbonate:1.1:
2；Formula (1) compound is 1 with formula (4) compound and the mol ratio of triethylamine:1.1:1.1.
Further, in step (2), the chiral amines catalyst is chiral secondary amine catalyst, preferably diaryl dried meat ammonia
Alcohol silicon ether.
Further, in step (2), the mol ratio of thiazoles substrate and formula (6) compound is 1：1.2.
Further, in step (3), compound shown in formula (I -1) and BFEE and triethyl group silicon hydrogen rub
You are than being 1：1.5：2.
Present invention also offers purposes of the above-claimed cpd in antineoplastic is prepared, the tumour is breast cancer, black
Melanoma.
The compounds process for production thereof of the present invention is easy, reaction is gentle, high income, and has certain antitumor activity,
With wide market application foreground.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, do not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The embodiment of form by the following examples, the above of the present invention is remake further specifically
It is bright.But the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Embodiment
The preparation of embodiment 1, the compounds of this invention
General synthetic routes 1：
Wherein, R1、R2It is independently selected from heterocycle, phenyl ring or there is substituent phenyl ring；R3For hydrogen.Be prepared with
Lower compound：
1st, the preparation of compound 001
(1) in round-bottomed flask, formula (1) thiobenzamide (1.0eq), dichloromethane (300ml), water are sequentially added
(100ml) and sodium acid carbonate (2.0eq).Round-bottomed flask is placed after stirring 15min, is slowly added dropwise chloracetyl chloride solution in ice bath
(1.1eq) (takes chloracetyl chloride to be dissolved in dichloromethane), and reaction is overnight.Reaction solution is extracted with dichloromethane after reaction, received
Collect organic layer, be concentrated and dried and can obtain formula (3) intermediate.
(2) in round-bottomed flask, add formula (3) intermediate and be dissolved in methanol (100ml), add first between formula (4)
Benzaldehyde (1.1eq) and triethylamine (1.1eq).Flow back 3h at 70 DEG C, recovers reaction solution to room temperature after the completion of reaction, dense
Contract to obtain crude product, by crude product with obtaining formula (5) thiazoles substrate after silica gel post separation.
(3) in a clean reaction tube, formula (5) thiazolone substrate (0.1mmol), acetaldehyde are sequentially added
(0.12mmol), diaryl dried meat ammonia alcohol silicon ether catalyst (0.02mmol), benzoic acid (0.02mmol), and tetrahydrofuran (1mL),
Stirred 12 hours at 25 DEG C, TLC monitoring raw material thiazolones disappear, and after reaction terminates, are removed under reduced pressure reaction dissolvent, on residue
Silicagel column, petroleum ether：Ethyl acetate=10:1 elution, thin layer tracking, merges eluent, removes solvent, produces two shown in formula (I)
Hydrogen pyrans and thiazole cycle compound, white solid, yield 93%, ee values 94%, mass spectrum (M+Na) 346.0880.
1H NMR(400MHz,CDCl3)δ7.89–7.67(m,2H),7.35–7.28(m,3H),7.20–7.14(m,1H),
7.04 (m, 3H), 5.73 (t, J=3.0Hz, 1H), 4.34 (dd, J=11.2,5.6Hz, 1H), 2.37-2.27 (m, 1H), 2.27
(d, J=3.6Hz, 3H), 2.03-1.96 (m, 1H)
13C NMR(100MHz,CDCl3)δ162.7,156.1,142.3,137.5,132.2,129.0,127.9,127.7,
127.4,127.2,124.5,123.8,108.0,92.3,36.0,33.8,20.4.
2nd, the preparation of compound 002
Preparation method need to only change tolualdehyde between formula (4) into p-tolualdehyde, produce compound with compound 001
002, white solid, yield 95%, ee values 86%, mass spectrum (M+Na) 346.0878.
1H NMR(600MHz,CDCl3)δ7.83–7.82(m,2H),7.38–7.36(m,3H),7.22–7.19(m,2H),
7.16-7.13 (m, 2H), 5.89 (t, J=3.0Hz, 1H), 4.37 (dd, J=10.8,3.6Hz, 1H), 2.42-2.36 (ddd, J
=13.8,6.0,3.0Hz, 1H), 2.35 (s, 3H), 2.17-1.99 (m, 1H)
13C NMR(150MHz,CDCl3)δ163.8,157.1,140.5,137.2,133.5,130.0,129.6,129.0,
127.7,125.7,109.1,93.4,37.1,34.5,21.2.
3rd, the preparation of compound 003
Preparation method need to only change tolualdehyde between formula (4) into 4-Fluorobenzaldehyde, produce compound with compound 001
003, white solid, yield 95%, ee values 90%, mass spectrum (M+Na) 350.0624.
1H NMR(400MHz,CDCl3)δ7.90–7.78(m,2H),7.46–7.34(m,3H),7.33–7.22(m,2H),
7.15-6.98 (m, 2H), 5.79 (t, J=2.4Hz, 1H), 4.45 (dd, J=11.2,5.6Hz, 1H), 2.39 (ddd, J=
13.6,5.6,2.4Hz,1H),2.06–1.99(m,1H).
13C NMR(150MHz,CDCl3)δ164.0,163.3,160.9,157.2,139.1,133.2,130.1,129.3,
129.2,129.0,125.5,115.8,115.6,108.7,93.2,37.1,34.3.
4th, the preparation of compound 004
Preparation method need to only change tolualdehyde between formula (4) into anisaldehyde, produce compound with compound 001
004, white solid, yield 94%, ee values 91%, mass spectrum (M+Na) 362.0824.
1H NMR(400MHz,CDCl3)δ7.92–7.77(m,2H),7.40–7.36(m,3H),7.32–7.17(m,2H),
6.97-6.79 (m, 2H), 5.79 (t, J=2.4Hz, 1H), 4.41 (dd, J=11.6,5.6Hz, 1H), 3.81 (s, 3H), 2.37
(ddd, J=13.6,5.6,2.4Hz, 1H), 2.07-2.00 (m, 1H)
13C NMR(100MHz,CDCl3)δ163.7,158.9,157.0,135.5,133.3,130.0,129.0,128.8,
125.6,114.2,109.5,93.3,55.313,37.1,34.1.
5th, the preparation of compound 005
Preparation method need to only change tolualdehyde between formula (4) into 4-chloro-benzaldehyde, produce compound with compound 001
005, white solid, yield 96%, ee values 90%, mass spectrum (M+Na) 366.0331.
1H NMR(600MHz,CDCl3)δ7.85–7.81(m,2H),7.39–7.36(m,3H),7.32–7.31(m,2H),
7.25 (m, 2H), 5.88 (t, J=2.4Hz, 1H), 4.38 (dd, J=11.4,5.4Hz, 1H), 2.41-2.36 (ddd, J=
13.2,5.4,2.4Hz,1H),2.08–2.01(m,1H).
13C NMR(150MHz,CDCl3)δ164.1,157.2,142.0,133.3,130.2,129.2,129.1,129.0,
125.7,108.1,95.7,93.2,37.1,34.5.
6th, the preparation of compound 006
Preparation method need to only change tolualdehyde between formula (4) into m chlorobenzaldehyde, produce compound with compound 001
006, white solid, yield 96%, yield 96%, ee values 94%, mass spectrum (M+H) 344.0510.
1H NMR(400MHz,CDCl3)δ7.83(m,2H),7.41–7.36(m,3H),7.32–7.27(m,3H),7.20–
7.18 (m, 1H), 5.90 (t, J=2.4Hz, 1H), 4.39 (dd, J=11.2,5.6Hz, 1H), 2.41 (ddd, J=13.6,
5.6,2.4Hz,1H),2.11–2.04(m,1H).
13C NMR(100MHz,CDCl3)δ164.2,157.2,145.5,134.7,133.2,130.1,128.9,127.9,
127.7,126.0,125.7,107.7,95.6,93.1,37.0,34.7.
7th, the preparation of compound 007
Preparation method need to only change tolualdehyde between formula (4) into methoxybenzaldehyde, produce compound with compound 001
007, white solid, yield 92%, ee values 95%, mass spectrum (M+Na) 362.0825.
1H NMR(400MHz,CDCl3)δ7.84–7.67(m,2H),7.32–7.28(m,3H),7.22–7.16(m,1H),
6.86-6.74 (m, 3H), 5.83 (t, J=2.4Hz, 1H), 4.31 (dd, J=11.2,5.6Hz, 1H), 3.72 (s, 3H), 2.34
(ddd, J=13.6,5.6,2.4Hz, 1H), 2.07-2.00 (m, 1H)
13C NMR(100MHz,CDCl3)δ163.9,159.9,157.1,145.1,133.3,130.0,129.9,128.9,
125.7,120.1,113.5,112.7,108.5,93.3,55.3,37.0,35.0.
8th, the preparation of compound 008
Preparation method need to only change tolualdehyde between formula (4) into p-bromobenzaldehyde, produce compound with compound 001
008, white solid, yield 95%, ee values 91%, mass spectrum (M+H) 388.0009.
1H NMR(400MHz,CDCl3)δ7.88–7.66(m,2H),7.44–7.36(m,2H),7.33–7.29(m,3H),
7.15-7.10 (m, 2H), 5.81 (t, J=2.4Hz, 1H), 4.30 (dd, J=11.2,5.6Hz, 1H), 2.32 (ddd, J=
13.2,5.6,2.4Hz,1H),2.01–1.94(m,1H).
13C NMR(100MHz,CDCl3)δ164.1,157.2,142.4,133.2,132.0,130.1,129.5,128.9,
125.7,121.3,107.9,93.1,37.0,34.5.
9th, the preparation of compound 009
Preparation method need to only change tolualdehyde between formula (4) into 3-bromobenzaldehyde, produce compound with compound 001
009, white solid, yield 94%, ee values 93%, mass spectrum (M+Na) 409.9828.
1H NMR(400MHz,CDCl3)δ7.78–7.74(m,2H),7.40–7.36(m,2H),7.32–7.28(m,3H),
7.18-7.11 (m, 2H), 5.83 (t, J=2.4Hz, 1H), 4.30 (dd, J=11.2,5.6Hz, 1H), 2.33 (ddd, J=
13.2,5.4,2.4Hz,1H),2.03–1.96(m,1H).
13C NMR(100MHz,CDCl3)δ164.2,157.3,145.8,133.2,130.8,130.6,130.4,130.1,
128.9,126.4,125.7,122.9,107.7,93.1,37.0,34.7.
10th, the preparation of compound 010
Preparation method need to only change tolualdehyde between formula (4) into 2- naphthalene benzaldehydes, produce compound with compound 001
010, white solid, yield 90%, ee values 93%, mass spectrum (M+Na) 382.0876.
1H NMR(400MHz,CDCl3)δ7.80–7.72(m,6H),7.45–7.38(m,2H),7.32–7.30(m,4H),
5.78 (t, J=2.4Hz, 1H), 4.56 (dd, J=11.2,5.6Hz, 1H), 2.40 (ddd, J=13.6,5.6,2.4Hz, 1H),
2.15–2.08(m,1H).
13C NMR(100MHz,CDCl3)δ162.9,156.2,139.7,132.4,132.2,131.8,129.0,127.9,
127.7,126.8,126.7,125.5,125.3,124.9,124.7,124.6,107.8,92.3,35.9,34.1.
11st, the preparation of compound 011
Preparation method need to only change tolualdehyde between formula (4) into paranitrobenzaldehyde, produce compound with compound 001
011, white solid, yield 88%, ee values 97%, mass spectrum (M+H) 355.0755.
1H NMR(600MHz,DMSO-d6) δ 8.16 (t, J=9.2Hz, 3H), 7.77 (q, J=4.6Hz, 2H), 7.65-
7.57 (m, 3H), 7.54 (d, J=8.6Hz, 1H), 7.40 (d, J=9.0Hz, 5H), 5.70 (s, 1H), 4.49 (dd, J=
10.4,5.8Hz, 1H), 2.46 (s, 1H), 2.30-2.18 (m, 1H), 2.00 (t, J=12.0Hz, 1H)
13C NMR(151MHz,CHLOROFORM-D)δ164.5,157.3,150.9,147.5,133.2,130.4,
129.0,128.8,125.8,124.3,106.6,93.0,36.9,35.0.
12nd, the preparation of compound 012
Preparation method need to be only changed tolualdehyde between formula (4) into methoxyl group m-hydroxybenzaldehyde, i.e., with compound 001
Obtain compound 012, white solid, yield 90%, ee values 93%, mass spectrum (M+Na) 378.0778.
1H NMR(400MHz,CDCl3)δ7.83–7.68(m,2H),7.30–7.28(m,3H),6.83–6.69(m,3H),
5.80 (t, J=2.4Hz, 1H), 4.23 (dd, J=11.2,5.6Hz, 1H), 3.81 (s, 3H), 2.30 (ddd, J=13.6,
5.6,2.8Hz,1H),2.03–1.96(m,1H).
13C NMR(150MHz,CDCl3)δ163.8,157.0,146.0,136.8,133.4,130.0,129.0,125.7,
119.3,114.0,110.9,109.2,93.4,56.1,37.1,34.3.
13rd, the preparation of compound 013
Preparation method need to only change tolualdehyde between formula (4) into thiazole carboxaldehyde, produce compound 013 with compound 001,
White solid, yield 82%, ee values 89%, mass spectrum (M+Na) 338.0287.
1H NMR(400MHz,CDCl3)δ7.80–7.76(m,2H),7.33–7.29(m,3H),7.18–7.14(m,1H),
6.95 (7-6.95m, 2H), 5.82 (t, J=2.8Hz, 1H), 4.68 (dd, J=10.8,5.6Hz, 1H), 2.42 (ddd, J=
13.6,5.6,3.2Hz,1H),2.22–2.07(m,1H).
13C NMR(100MHz,CDCl3)δ162.9,155.5,145.8,132.2,129.0,127.9,125.8,124.6,
124.0,123.4,107.5,92.2,36.4,29.3.
14th, the preparation of compound 014
Preparation method changes formula (1) thiobenzamide into thiophene -2- thioformamides, by formula (4) with compound 001
Between tolualdehyde change benzaldehyde into, produce compound 014, white solid, yield 63%, ee values 86%, mass spectrum (M+Na)
338.0287。
1H NMR(400MHz,DMSO-d6)δ7.94–7.84(m,1H),7.80–7.70(m,2H),7.60–7.55(m,
4H), 7.53-7.51 (m, 2H), 7.32 (dd, J=5.6,3.6Hz, 1H), 5.95-5.93 (m, 1H), 4.53 (dd, J=11.2,
5.6Hz, 1H), 2.43 (ddd, J=13.2,5.6,3.2Hz, 1H), 2.30-2.16 (m, 1H)
13C NMR(150MHz,CDCl3)δ157.8,156.5,143.4,137.4,129.0,127.9,127.8,127.6,
127.6,125.9,108.0,93.3,37.0,34.9.
15th, the preparation of compound 015
Preparation method need to only change formula (1) thiophene -2- thioformamides into 3- tolyls thio formyl with compound 014
Amine, produce compound 015, white solid, yield 90%, ee values 95%, mass spectrum (M+Na) 346.0877.
1H NMR(400MHz,CDCl3) δ 7.68-7.60 (m, 2H), 7.36-7.27 (m, 6H), 7.17 (d, J=7.6Hz,
1H), 5.89 (t, J=2.4Hz, 1H), 4.40 (dd, J=11.2,5.6Hz, 1H), 2.41 (ddd, J=13.6,5.6,2.8Hz,
1H),2.35(s,3H),2.14–2.07(m,1H).
13C NMR(150MHz,CDCl3)δ164.1,157.1,143.6,138.7,133.3,130.9,128.9,128.9,
127.9,127.5,126.4,122.9,108.6,93.3,37.1,34.9,21.4.
16th, the preparation of compound 016
Preparation method need to be only changed formula (1) thiophene -2- thioformamides to bromine thiobenzamide into compound 014,
Produce compound 016, white solid, yield 90%, ee values 91%, mass spectrum (M+Na) 409.9824.
1H NMR(400MHz,CDCl3)δ7.71–7.66(m,2H),7.52–7.48(m,2H),7.38–7.29(m,5H),
5.90 (t, J=2.4Hz, 1H), 4.39 (dd, J=11.2,5.6Hz, 1H), 2.41 (ddd, J=13.6,5.6,2.8Hz, 1H),
2.14–2.07(m,1H).
13C NMR(150MHz,CDCl3)δ162.5,157.3,143.3,132.2,129.0,127.8,127.6,127.1,
124.3,109.4,96.1,93.4,37.0,34.9.
The preparation of embodiment 2, the compounds of this invention
General synthetic routes 2：
Wherein, R1、R2It is independently selected from heterocycle, phenyl ring or there is substituent phenyl ring；R3For C1-C10Alkane or phenyl ring.
Following compound has been prepared：
1st, the preparation of compound 017
(1) in round-bottomed flask, formula (1) thiobenzamide (1.0eq), dichloromethane (300ml), water are sequentially added
(100ml) and sodium acid carbonate (2.0eq).Round-bottomed flask is placed after stirring 15min, is slowly added dropwise chloracetyl chloride solution in ice bath
(1.1eq) (takes chloracetyl chloride to be dissolved in dichloromethane), and reaction is overnight.Reaction solution is extracted with dichloromethane after reaction, received
Collect organic layer, be concentrated and dried and can obtain formula (3) intermediate.
(2) in round-bottomed flask, add formula (3) intermediate and be dissolved in methanol (100ml), add formula (4) benzene first
Aldehyde (1.1eq) and triethylamine (1.1eq).Flow back 3h at 70 DEG C, recovers to room temperature reaction solution after the completion of reaction, is concentrated to give
Crude product, by crude product with obtaining formula (5) thiazoles substrate after silica gel post separation.
(3) in a clean reaction tube, formula (5) thiazolone substrate (0.1mmol), propionic aldehyde are sequentially added
(0.12mmol), diaryl dried meat ammonia alcohol silicon ether catalyst (0.02mmol), benzoic acid (0.02mmol), and tetrahydrofuran (1mL),
Stirred 12 hours at 25 DEG C, TLC monitoring raw material thiazolones disappear, and after reaction terminates, are removed under reduced pressure reaction dissolvent, on residue
Silicagel column, petroleum ether：Ethyl acetate=10:1 elution, thin layer tracking, merges eluent, removes solvent, and obtained product is molten
In dichloromethane (1ml), BFEE (0.2mmol) and triethyl group silicon hydrogen (0.3mmol) are added, 2 are stirred at 25 DEG C
Hour, TLC monitoring intermediate products disappear, and after reaction terminates, reaction dissolvent are removed under reduced pressure, silicagel column purifies on residue, produces
Formula (I) dihydropyran and thiazole cycle compound, white solid, yield 92%, ee values 98%, mass spectrum (M+Na) 330.0930.
1H NMR(400MHz,CDCl3)δ7.88–7.82(m,2H),7.39–7.27(m,6H),7.24–7.19(m,2H),
4.36 (dd, J=11.2,3.2Hz, 1H), 4.02 (dd, J=11.2,9.6Hz, 1H), 3.73 (d, J=8.4Hz, 1H),
2.23m, 1H), 1.00 (d, J=6.8Hz, 3H)
13C NMR(100MHz,CDCl3)δ163.8,159.9,143.4,133.6,129.9,128.8,128.6,128.2,
127.4,125.6,108.2,72.2,46.5,36.8,15.0.
2nd, the preparation of compound 018
Preparation method need to only change formula (4) benzaldehyde into p-tolualdehyde, produce compound 018, in vain with compound 017
Color solid, yield 93%, ee values 98%, mass spectrum (M+Na) 344.1082.
1H NMR(400MHz,CDCl3)δ7.86–7.71(m,2H),7.31–7.27(m,3H),7.10–7.01(m,4H),
4.29 (dd, J=11.2,3.2Hz, 1H), 3.93 (dd, J=11.2,9.6Hz, 1H), 3.62 (d, J=8.4Hz, 1H), 2.28
(s, 3H), 2.20-2.07 (m, 1H), 0.92 (d, J=6.8Hz, 3H)
13C NMR(150MHz,CDCl3)δ163.8,159.9,140.5,137.2,133.7,129.9,129.4,128.9,
128.2,125.7,108.7,100.0,72.3,46.2,36.9,21.2,15.0.
3rd, the preparation of compound 019
Preparation method need to only change formula (4) benzaldehyde into 4-chloro-benzaldehyde, produce compound 019, in vain with compound 017
Color solid, yield 94%, ee values 98%, mass spectrum (M+Na) 364.0537.
1H NMR(400MHz,CDCl3)δ7.84–7.71(m,2H),7.34–7.27(m,3H),7.26–7.20(m,2H),
7.12-7.04 (m, 2H), 4.27 (dd, J=11.2,3.2Hz, 1H), 3.93 (dd, J=11.2,9.6Hz, 1H), 3.63 (d, J
=8.4Hz, 1H), 2.16-2.06 (m, 1H), 0.91 (d, J=6.8Hz, 3H)
13C NMR(100MHz,CDCl3)δ163.0,159.0,140.8,132.4,132.1,129.0,128.5,127.8,
127.8,124.6,106.5,71.0,44.9,35.8,13.8.
4th, the preparation of compound 020
Preparation method need to only change formula (4) benzaldehyde into anisaldehyde, produce compound 020 with compound 017,
White solid, yield 95%, ee values 96%, mass spectrum (M+Na) 360.1043.
1H NMR(400MHz,CDCl3)δ7.93–7.76(m,2H),7.45–7.33(m,3H),7.21–7.08(m,2H),
6.91-6.81 (m, 2H), 4.36 (dd, J=11.2,3.2Hz, 1H), 4.00 (dd, J=11.2,9.6Hz, 1H), 3.81 (s,
3H), 3.68 (d, J=8.4Hz, 1H), 2.24-2.14 (m, 1H), 0.99 (d, J=6.8Hz, 3H)
13C NMR(100MHz,CDCl3)δ163.6,159.8,158.8,135.4,133.6,129.8,129.2,128.8,
125.6,114.0,108.8,72.3,55.3,45.8,36.9,14.9.
5th, the preparation of compound 021
Preparation method need to only change formula (4) benzaldehyde into p-bromobenzaldehyde, produce compound 021, in vain with compound 017
Color solid, yield 92%, ee values 99%, mass spectrum (M+Na) 408.0033.
1H NMR(400MHz,CDCl3)δ7.93–7.79(m,2H),7.51–7.43(m,2H),7.42–7.33(m,3H),
7.17-7.02 (m, 2H), 4.35 (dd, J=11.2,3.2Hz, 1H), 4.01 (dd, J=11.2,9.6Hz, 1H), 3.70 (d, J
=8.4Hz, 1H), 2.19-2.14 (m, 1H), 1.00 (d, J=6.8Hz, 3H)
13C NMR(150MHz,CDCl3)δ164.1,160.1,142.5,131.9,130.1,130.0,128.9,125.7,
121.3,107.5,72.2,46.1,36.9,29.8,14.9.
6th, the preparation of compound 022
Preparation method need to only change formula (4) benzaldehyde into tolualdehyde, produce compound 022, in vain with compound 017
Color solid, yield 93%, ee values 99%, mass spectrum (M+Na) 344.1086.
1H NMR(400MHz,CDCl3)δ7.86–7.72(m,2H),7.33–7.25(m,3H),7.16–7.13(m,1H),
7.03-7.01 (m, 1H), 6.95-6.93 (m, 2H), 4.28 (dd, J=11.2,3.2Hz, 1H), 3.93 (dd, J=11.2,
9.6Hz, 1H), 3.62 (d, J=8.4Hz, 1H), 2.27 (s, 3H), 2.25-2.18 (m, 1H), 0.93 (d, J=6.8Hz, 3H)
13C NMR(150MHz,CDCl3)δ163.8,159.9,143.4,138.4,133.7,129.9,128.9,128.9,
128.6,128.2,125.7,125.4,108.5,72.3,46.5,36.8,21.6,15.1.
7th, the preparation of compound 023
Preparation method need to only change formula (4) benzaldehyde into methoxybenzaldehyde, produce compound 023 with compound 017,
White solid, yield 94%, ee values 95%, mass spectrum (M+Na) 360.1032.
1H NMR(400MHz,CDCl3)δ7.85–7.72(m,2H),7.34–7.25(m,3H),7.16–7.14(m,1H),
7.04-7.00 (m, 2H), 6.95-6.93 (m, 1H), 4.28 (dd, J=11.2,3.2Hz, 1H), 3.93 (dd, J=11.2,
9.6Hz, 1H), 3.62 (d, J=8.4Hz, 1H), 2.27 (s, 3H), 2.28-2.19 (m, 1H), 0.93 (d, J=6.8Hz, 3H)
13C NMR(150MHz,CDCl3)δ163.8,159.9,145.0,133.6,129.9,129.6,128.8,125.6,
120.6,114.0,112.6,108.1,72.2,55.3,46.5,36.6,15.0.
8th, the preparation of compound 024
Preparation method need to only change formula (4) benzaldehyde into m chlorobenzaldehyde, produce compound 024, in vain with compound 017
Color solid, yield 95%, ee values 99%, mass spectrum (M+Na) 364.0539.
1H NMR(400MHz,CDCl3)δ7.97–7.64(m,2H),7.36–7.25(m,3H),7.24–7.16(m,2H),
7.15-7.12 (m, 1H), 7.08-6.97 (m, 1H), 4.28 (dd, J=11.2,3.2Hz, 1H), 3.94 (dd, J=11.2,
9.6Hz, 1H), 3.64 (d, J=8.4Hz, 1H), 2.19-2.09 (m, 1H), 0.94 (d, J=6.8Hz, 3H)
13C NMR(100MHz,CDCl3)δ164.1,160.0,145.5,134.6,133.5,130.0,130.0,128.8,
128.3,127.7,126.4,125.7,107.2,72.0,46.2,36.8,15.0.
9th, the preparation of compound 025
Preparation method need to only change formula (4) benzaldehyde into o-chlorobenzaldehyde, produce compound 025, in vain with compound 017
Color solid, yield 91%, ee values 99%, mass spectrum (M+Na) 364.0538.
1H NMR(400MHz,CDCl3)δ7.88–7.85(m,2H),7.45–7.35(m,4H),7.23–7.21(m,2H),
7.17-7.10 (m, 1H), 4.37 (d, J=5.6Hz, 1H), 4.27-4.21 (m, 1H), 4.06 (dd, J=11.2,6.8Hz,
1H), 2.28-2.22 (m, 1H), 1.16 (d, J=6.8Hz, 3H)
13C NMR(150MHz,CDCl3)δ164.1,160.2,141.4,133.8,133.6,130.1,129.8,128.9,
128.5,127.3,125.8,105.5,70.6,35.7,15.9,12.5.
10th, the preparation of compound 026
Preparation method need to only change formula (4) benzaldehyde into 2- naphthalene benzaldehydes, produce compound 026, in vain with compound 017
Color solid, yield 94%, ee values 98%, mass spectrum (M+Na) 380.1081.
1H NMR(400MHz,CDCl3)δ7.81–7.71(m,5H),7.64–7.60(m,1H),7.42–7.40(m,2H),
7.32-7.22 (m, 4H), 4.33 (dd, J=11.2,3.2Hz, 1H), 3.99 (dd, J=11.2,9.6Hz, 1H), 3.83 (d, J
=8.4Hz, 1H), 2.29-2.27 (m, 1H), 0.96 (d, J=6.8Hz, 3H)
13C NMR(150MHz,CDCl3)δ164.0,160.1,140.8,133.6,133.6,132.9,130.0,128.9,
128.7,127.9,127.8,127.4,126.4,126.1,125.9,125.7,108.2,72.3,46.8,36.7,15.1.
11st, the preparation of compound 027
Preparation method need to only change formula (4) benzaldehyde into paranitrobenzaldehyde, produce compound 027 with compound 017,
White solid, yield 88%, ee values 98%, mass spectrum (M+Na) 375.0779.
1H NMR(600MHz,CDCl3) δ 8.20 (d, J=9.0Hz, 2H), 7.89-7.77 (m, 2H), 7.38 (d, J=
9.6Hz, 5H), 4.35 (d, J=10.8Hz, 1H), 4.03 (dd, J=10.8,9.6Hz, 1H), 3.86 (d, J=8.4Hz, 1H),
2.29-2.14 (m, 1H), 1.01 (d, J=6.6Hz, 3H)
13C NMR(150MHz,CDCl3)δ164.6,160.3,150.9,147.4,133.3,130.3,129.2,129.0,
125.8,124.1,106.2,72.0,46.4,37.0,15.0.
12nd, the preparation of compound 028
Preparation method need to only change formula (4) benzaldehyde into 3-bromobenzaldehyde, produce compound 028, in vain with compound 017
Color solid, yield 93%, ee values 97%, mass spectrum (M+Na) 408.0034.
1H NMR(600MHz,CDCl3)δ7.86–7.83(m,2H),7.43–7.40(m,1H),7.39–7.35(m,4H)
7.21 (t, J=7.8Hz, 1H), 7.14 (d, J=7.8,1H), 4.34 (dd, J=10.8,3.0Hz, 1H), 4.03 (dd, J=
11.4,9.6Hz, 1H), 3.70 (d, J=8.4Hz, 1H), 2.25-2.17 (m, 1H), 1.01 (d, J=6.6Hz, 3H)
13C NMR(150MHz,CDCl3)δ164.2,160.1,145.8,133.5,131.3,130.7,130.3,130.1,
128.9,126.9,125.8,122.9,107.2,72.0,46.3,36.9,15.1.
13rd, the preparation of compound 029
Preparation method need to only change formula (4) benzaldehyde into 4-Fluorobenzaldehyde, produce compound 029, in vain with compound 017
Color solid, yield 91%, ee values 99%, mass spectrum (M+Na) 348.0834.
1H NMR(600MHz,CDCl3) δ 7.92-7.76 (m, 2H), 7.38-7.34 (m, 3H), 7.17 (dd, J=8.4,
5.4Hz, 2H), 7.01 (t, J=8.4Hz, 2H), 4.35 ((dd, J=10.8,3.0Hz, 1H), 4.00 (t, J=10.8Hz,
1H), 3.71 (d, J=8.4Hz, 1H), 2.23-2.09 (m, 1H), 1.00-0.95 (d, J=7.2Hz, 3H)
13C NMR(150MHz,CDCl3)δ164.0,162.9,161.3,160.0,139.1,133.6,130.1,129.8,
129.7,128.9,125.7,115.7,115.5,108.1,72.2,45.9,37.0,14.9.
14th, the preparation of compound 030
Preparation method need to only change formula (4) benzaldehyde to methoxyl group m-hydroxybenzaldehyde, producing into compound 017
Compound 030, white solid, yield 87%, ee values 95%, mass spectrum (M+Na) 376.983.
1H NMR(600MHz,CDCl3)δ7.92–7.76(m,2H),7.41–7.30(m,3H),6.83–6.74(m,2H),
6.75-6.64 (m, 1H), 5.75 (s, 1H), 4.33 (d, J=11.4Hz, 1H), 3.97 (t, J=10.8Hz, 1H), 3.87 (s,
3H), 3.61 (d, J=8.4Hz, 1H), 2.19-2.17 (m, 1H), 0.97 (d, J=6.6Hz, 3H)
13C NMR(150MHz,CDCl3)δ163.7,159.8,145.9,145.8,136.7,133.7,129.9,128.9,
125.7,119.8,114.4,110.6,108.7,72.3,56.0,46.0,36.8,15.0.
15th, the preparation of compound 031
Preparation method changes formula (4) benzaldehyde into 4-chloro-benzaldehyde, the propionic aldehyde in step (3) is changed into compound 017
Butyraldehyde, produce compound 031, white solid, yield 92%, ee values 94%, mass spectrum (M+H) 356.0874.
1H NMR(600MHz,CDCl3) δ 7.89-7.80 (m, 2H), 7.37 (s, 3H), 7.30 (d, J=8.4Hz, 2H),
7.14 (d, J=8.4Hz, 2H), 4.39 (d, J=11.4Hz, 1H), 4.09-4.02 (m, 1H), 3.84 (d, J=8.4Hz, 1H),
1.99–1.90(m,1H),1.59–1.50(m,1H),1.34(m,1H),1.01–0.93(m,3H).
13C NMR(150MHz,CDCl3)δ164.1,160.1,142.5,133.5,133.1,130.6,130.1,129.6,
128.9,125.7,107.2,69.4,43.8,43.4,22.8,11.8.
16th, the preparation of compound 032
Preparation method need to only change the butyraldehyde in step (3) into valeraldehyde, produce compound 032, in vain with compound 031
Color solid, yield 93%, ee values 96%, mass spectrum (M+H) 370.1034.
1H NMR(600MHz,CDCl3) δ 7.84 (d, J=4.8Hz, 2H), 7.39-7.35 (m, 3H), 7.30 (d, J=
8.4Hz, 2H), 7.14 (d, J=8.4Hz, 2H), 4.37 (d, J=9.6Hz, 1H), 4.11-4.00 (m, 1H), 3.82 (d, J=
8.4Hz, 1H), 2.02 (d, J=9.6Hz, 1H), 1.43 (d, J=9.6Hz, 2H), 1.33-1.24 (m, 2H), 0.88-0.83
(m,3H).
13C NMR(150MHz,CDCl3)δ164.1,160.0,142.5,133.5,133.1,130.1,129.6,128.9,
128.5,125.7,107.1,69.7,44.1,41.5,32.2,20.4,14.2.
17th, the preparation of compound 033
Preparation method need to only change the butyraldehyde in step (3) into n-hexyl aldehyde, produce compound 033, in vain with compound 031
Color solid, yield 92%, ee values 94%, mass spectrum (M+H) 384.1188.
1H NMR(600MHz,CDCl3) δ 7.88-7.80 (m, 2H), 7.38-7.36 (m, 3H), 7.30 (d, J=8.4Hz,
2H), 7.13 (d, J=8.4Hz, 2H), 4.37 (d, J=10.8Hz, 1H), 4.06-4.01 (m, 1H), 3.82 (d, J=9.6Hz,
1H), 2.01-1.99 (m, 1H), 1.52-1.13 (m, 6H), 0.83 (d, J=8.4Hz, 3H)
13C NMR(150MHz,CDCl3)δ164.1,160.0,142.5,133.5,133.1,130.1,129.6,128.9,
128.5,125.7,107.1,69.7,44.1,41.7,29.7,29.4,22.8,14.0.
18th, the preparation of compound 034
Preparation method need to only change the butyraldehyde in step (3) into n-Heptaldehyde, produce compound 034, in vain with compound 031
Color solid, yield 89%, ee values 90%, mass spectrum (M+H) 398.1344.
1H NMR(600MHz,CDCl3)δ7.85–7.83(m,2H),7.38–7.36(m,3H),7.31–7.29(m,2H),
7.15-7.13 (m, 2H), 4.37 (d, J=11.4Hz, 1H), 4.08-4.00 (m, 1H), 3.81 (d, J=7.8Hz, 1H),
2.01-1.99 (m, 1H), 1.51-1.14 (m, 8H), 0.84 (dd, J=8.4,5.4Hz, 3H)
13C NMR(150MHz,CDCl3)δ164.1,160.0,142.5,133.5,133.1,130.1,129.6,128.9,
128.5,125.7,107.1,69.7,44.1,41.8,31.9,29.9,26.9,22.6,14.1.
19th, the preparation of compound 035
Preparation method need to only change the butyraldehyde in step (3) into phenylacetaldehyde, produce compound 035, in vain with compound 031
Color solid, yield 90%, ee values 94%, mass spectrum (M+Na) 418.1033.
1H NMR(600MHz,CDCl3)δ7.90–7.84(m,2H),7.39–7.37(m,4H),7.32–7.28(m,4H),
7.16-7.09 (m, 4H), 4.22 (d, J=11.4Hz, 1H), 4.08-4.03 (m, 1H), 3.93 (d, J=5.4Hz, 1H), 2.86
(m,1H),2.68–2.59(m,1H),2.31–2.29(m,1H).
13C NMR(150MHz,CDCl3)δ164.4,159.9,142.6,138.9,133.5,133.2,130.2,129.5,
129.1,129.0,129.0,128.8,126.7,125.8,105.9,68.3,43.8,42.8,36.7.
Beneficial effects of the present invention are illustrated below by way of test example.
Test example 1, antitumor research
1st, experimental tumor cell line
Human breast carcinoma MB468 cell lines, human breast carcinoma SKBR3 cell lines, human breast carcinoma MB231 cell lines, mouse black
Plain knurl A375 cell lines are provided by biological therapy National Key Laboratory of Sichuan University, and above tumour cell is frozen in Sichuan
Biological therapy National Key Laboratory of university.
2nd, experimental method
The preparation and processing of 2.1 cells
4 kinds of tumour cells are incubated at the RPMI-1640 nutrient solutions containing 10% inactivation newborn calf serum, 37 DEG C, 5%
CO280% cell fusion is grown in incubator, is digested with 0.1% trypsin solution, single cell suspension is made, adjusts cell concentration
For 5 × 104/mL, be uniformly inoculated in 96 hole microtest plates, every group of 3 multiple holes, 100 μ l/ holes, put 37 DEG C of saturated humidities,
5%CO2In incubator after culture 24h, Normal group adds the nutrient solution containing equivalent；Add the test medicine of concentration gradient
(100,50,25,12.5,6.25 μ g/mL), each concentration set 3 multiple holes, and experiment is parallel 2 times.Treat medicine and cytosis 24h
Afterwards, 10 μ L MTT solution (5mg/mL) are added per hole, continue to add 100 μ L DMSO per hole after cultivating 4h, vibration mixes, and makes knot
Brilliant thing is fully dissolved, and its absorbance (A values) is surveyed at ELIASA 490nm wavelength, and each concentration group takes its average value.
The measure of 2.2 Cytostatic to tumor cell rates
Cell proliferation inhibition rate is calculated by following equation：Cell proliferation inhibition rate (%)=(1- test groups A values/control group
A values) × 100%.All experimental datas carry out statistical analysis using SPSS 13.0.Experimental result tries to achieve IC using Probit50
Value.
3rd, experimental result
The suppression situation that the compounds of this invention of table 1 grows to subject cell
Test result indicates that the compounds of this invention has certain antitumous effect.
In summary, the preparation method of the compounds of this invention is easy, reaction is gentle, high income, and with certain anti-
Tumor promotion, there is wide market application foreground.
Claims (10)
- A kind of 1. dihydropyran and thiazole cycle compound or its crystal as shown in formula (I)：Wherein, R1、R2It is independently selected from heterocycle, phenyl ring or there is substituent phenyl ring；R3For hydrogen, C1-C10Alkane or phenyl ring；R4For hydrogen or hydroxyl.
- 2. compound according to claim 1, the compound has formula (I -1) or formula (I -2) structure：
- 3. compound according to claim 1, the compound is one of following compound：
- 4. the preparation method of any one of the claim 1-3 compounds, it is characterised in that：Comprise the following steps：(1) modus ponens (1) compound, chloracetyl chloride and sodium acid carbonate, with dichloromethane：Water=3:1 is solvent, at 0 ± 3 DEG C Reaction, produces formula (3) intermediate；Formula (4) compound and triethylamine are added into formula (3) intermediate, after 70 ± 3 DEG C of reactions, Produce formula (5) thiazoles substrate；(2) modus ponens (5) thiazoles substrate, formula (6) compound and chiral amines catalyst, with tetrahydrofuran：Water=10:1 is molten Agent, after 25 ± 3 DEG C of reactions, produce compound shown in formula (I -1)；(3) compound, BFEE and triethyl group silicon hydrogen shown in modus ponens (I -1), react at 25 ± 3 DEG C, produce formula (I - 2) compound shown in.
- 5. according to the method for claim 4, it is characterised in that：R1、R2It is independently selected from heterocycle, phenyl ring or has and takes For base phenyl ring；R3For hydrogen, C1-C10Alkane or phenyl ring.
- 6. the method according to claim 4 or 5, it is characterised in that：In step (1), formula (1) compound and chloracetyl chloride with And the mol ratio of sodium acid carbonate is 1:1.1:2；Formula (1) compound is 1 with formula (4) compound and the mol ratio of triethylamine: 1.1:1.1。
- 7. according to the preparation method described in claim any one of 4-6.It is characterized in that：In step (2), the chiral amine is urged Agent is chiral secondary amine catalyst, preferably diaryl dried meat ammonia alcohol silicon ether.
- 8. according to the preparation method described in claim any one of 4-7.It is characterized in that：In step (2), thiazoles substrate and formula (6) mol ratio of compound is 1：1.2.
- 9. according to the preparation method described in claim any one of 4-8.It is characterized in that：In step (3), formula (I -1) shownization Compound is 1 with the mol ratio of BFEE and triethyl group silicon hydrogen：1.5：2.
- 10. purposes of the compound described in claim any one of 1-3 in antineoplastic is prepared, the tumour is mammary gland Cancer, melanoma.
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| CN105992764A (en) * | 2013-10-17 | 2016-10-05 | 艾伯维德国有限责任两合公司 | Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy |
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| CN109674790A (en) * | 2019-02-12 | 2019-04-26 | 兰州大学 | Thiazole and the application in preparing anti-inflammatory drugs of pyranone analog |
| CN109674790B (en) * | 2019-02-12 | 2021-06-29 | 兰州大学 | Application of thiazolopyrone analogs in the preparation of anti-inflammatory drugs |
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